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Effect of High Fructose Diet on Mouse Behavior

By December 28, 2017August 4th, 2019No Comments

In a previous topic, we discussed the adverse effects of overconsumption of saturated fatty acids which are a common component of the Western diet. Now, we will examine the other side of the coin, a diet that is too high in simple carbohydrates, more specifically: a high fructose diet.

Sugar is becoming a leading ingredient in the contemporary diet and is readily available in many forms, from chocolates to ice creams to pastries to frappucinos. Chances are you had some today, but do you know how exactly sugar impacts cognition and your physiology?

Animal studies are being used to study how sugars affect various developmental and physiological conditions.

Types of Sugar

Before we assess these animal and behavioral studies, along with the insights they give, let’s take a pause and quickly review the molecule of interest here: sugar.

Sugar is a general term that can refer to a wide array of carbohydrates, including monosaccharides, disaccharides, and oligosaccharides.

Examples of monosaccharides include glucose, fructose, and galactose. Fructose is often confused with high fructose corn syrup (HFCS), simply because they share a similar name.

However, fructose and HFCS are different entities. While fructose is a naturally occurring compound found in fruits, HFCS is manufactured from corn syrup. Corn syrup naturally contains both glucose and fructose (with a  higher proportion of glucose). To become HFCS, it goes through a chemical process which alters its chemical composition, making fructose in greater concentration by converting some of the glucose molecules into fructose.

The most classic example of a disaccharide is table sugar, also known as sucrose. Sucrose is a combination of glucose and fructose in a 50:50 ratio.

High fructose corn syrup-55 (HFCS-55), on the other hand, has a ratio of 55:42 of fructose to

glucose[1]. Other types of HFCS, such as HFCS-42, HFCS-65, and HFCS-90, exist and have a different ratio of fructose to glucose. But, the HFCS-55 is by far the most common type.

High Fructose Diet

You can find high fructose corn syrup in just about anything because it is cheap to produce and tastes sweeter than an equal portion with sucrose.

In fact, one of the most popular sweeteners in the United States is high fructose corn syrup[1]. Sweeteners are especially common in beverages and sodas which, in turn, are being consumed with greater frequency in the recent decades.

While the effect of high fat and high sugar diets has been established as negatively impacting metabolism, much less is known about the corresponding effects on cognition.

High fructose corn syrup affects adolescent rats’ hippocampus

Hsu et al. demonstrated that a diet full of high fructose corn syrup-55 (HFCS-55) will negatively affect adolescent rats’ hippocampus by triggering neuroinflammation. The study was designed to compare the effects of sugar intake on rats that are in different stages of development, in order to determine whether fructose or sucrose affect adolescent rats differently than adult rats[1].

The adolescent rats that consumed HFCS-55

  • Performed poorly in a Barnes maze, demonstrating the inability to form spatial memory; a process that depends on the hippocampus
  • Showed pro-inflammatory cytokines (interleukin 1β and interleukin 6) as marked protein expressions in the dorsal hippocampus.

By comparison, the adult rats did not show such dramatic differences when consuming a high fructose diet, at least in this particular study.

To isolate the behaviors to the hippocampus, the researchers used two other behavioral procedures:

  • A zero maze was used to determine whether any anxiety effects could possibly be associated with high fructose consumption.
  • Also, a response task (Y-maze) was used to determine whether non-hippocampal specific learning would be affected by a diet high in fructose.

Translational Research

What is known

Obesity negatively impacts human cognition

Bruggeman et al. demonstrated that a high fructose diet does not affect female rats when it comes to drug reinforcement learning[2].

The experimental rats were given a 60% fructose diet because this is the standard protocol that elicits the spatial memory deficits in both adult and adolescent rats.

Then, in order to expose the rats to drugs and create the conditions for reinforcement learning, the researchers created several experimental conditions and schedules for which to administer amphetamine in a controlled fashion.

To test the effects of the factors at hand (the interaction between high fructose diet and drug reinforcement learning) the rats went through several behavioral tests and challenges, such as:

In order to ensure that the learning and behavioral performance weren’t affected by amphetamine, the researchers included a second level to their experiment which didn’t include drug administration.

The results demonstrated that neither drug-reinforcement learning nor spatial learning was affected by a high fructose diet.

To explain these surprising results, estrogen was brought into question because one way that female rats differ significantly from male rats is in terms of the hormone estrogen.

Estrogen has a protective role in the hippocampus and previous studies have shown that estrogen administration can help reverse some working memory deficits if given to male rats that have streptozotocin-induced diabetes[3]. Also, ovariectomized female mice will do better in the spatial water maze when given estrogen supplements[4].

Exploring the interplay between HFCS, cognition, and gender

There are countless studies, reviews, and analyses that demonstrate the strong link between poor performance in neuropsychological tests and being overweight or obese in adults and children[5].

The negative impact of obesity on cognition also translates to the elderly, defined as being over 65 years of age[6].

Research by Papanikolaou et al. demonstrates that just a single meal can affect the cognitive performance of type 2 diabetics. Following an overnight fast, participants were given either pasta to eat (which has a low glycaemic index) or white bread (which has a high glycaemic index). Then, their plasma glucose concentrations were measured and neuropsychological tests were given. The group that had a low glycaemic index meal (the pasta) had better verbal memory. While those that ate the white bread performed poorer on the measures of executive function, working memory, sustained attention, and auditory selective attention[7]. This experiment is significant as it demonstrates that intake of carbohydrates which increase blood sugar can quickly and dramatically affect cognitive function[7]. Although the exact mechanism behind this remains unknown, the decrease in cognitive functions is believed to occur because neurons in areas of the brain (such as the hippocampus) that are important for cognition are sensitive to blood insulin levels, which are in turn related to blood glucose levels.

A similar approach was taken when determining the effect of low versus high glycaemic index cereal on healthy adolescents’ verbal episodic memory. Under conditions that induced divided attention, participants from each group had to remember certain items. The forgetting index was much higher in the group that consumed a high glycaemic index cereal meal[8].

What remains unknown

It remains an open question whether the sex-dependent differences observed by Bruggeman et al. will be found in humans, whether men and women are affected differently by high fructose diet. Bruggeman et al. suggest that further studies on the interaction between estrogen and spatial-memory must be conducted, in order to determine whether estrogen has possible protective factors that shield the organism from damage otherwise caused by a high fructose diet[2].

Underlying Mechanisms

Another open question pertains to the underlying mechanisms associated with the memory deficits induced by a high fructose diet.

One theory explains the cognitive deficits by pointing to the ways that high sugar consumption affects the vascular system[9]. The body produces fat out of excess sugar, in order to store energy. The excess sugar is stored as adipose tissue which in turn affects the vascular system. Adipose tissue secretes many molecules, such as resistin, leptin, and cytokines. Leptin is a hormone that can enter the bloodstream and affect the hypothalamus by urging it to induce sympathetic activity. Prolonged sympathetic activation leads to hypertension which in turn affects cognitive functioning[11].

Current research suggests that brain-derived neurotrophic factor (BDNF) is implicated in many eating disorders and cognitive functions, suggesting a link between food consumption and mental ability. Also, this line of research is beginning to explore the hereditary nature and behavioral profile. Interestingly enough, this protein is implicated in memory performance and subsequently impacted by obesity, since both share the hippocampus as an area of common interest[10].

Also, it still remains an open question whether mechanisms and functions that are otherwise independent of the hippocampus would be impacted by a high fructose diet at all[2].


Diets high in fructose are harmful and unhealthy when consumed in excess. In addition to saturated fats, these sugars (or simple carbohydrates) are becoming increasingly popular, earning the title “the Western Diet”.

HFCS is a common sweetener found in many foods, especially in sodas and sweetened beverages. Notably, these food items are being consumed at a higher rate than ever before.
Such dietary choices impact health and are associated with not only changes in body weight and metabolism, but also in cognition.

A higher intake of fructose and sugars impacts the adolescents’ physiology and creates inflammation in the hippocampus which in turn influences performance on spatial tests.

As outlined in the translational research section, the impact of food on cognition is visible just after a single meal with effects as powerful as significant differences on verbal memory tests[7].

However, much remains unknown. Out of many areas for future research, two important directions include: understanding the gender differences in behavior after consuming a high fructose diet and determining the etiology of these cognitive effects. Fortunately, both can be explored through the good use of animal models.


  1. Hsu, Ted M., et al. “Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats.” Hippocampus 25.2 (2015): 227-239.
  2. Bruggeman, Emily C., et al. “A high fructose diet does not affect amphetamine self-administration or spatial water maze learning and memory in female rats.” Pharmacology Biochemistry and Behavior 99.3 (2011): 356-364.
  3. Lannert, H., et al. “Effects of Estradiol (− 17β) on learning, memory and cerebral energy metabolism in male rats after intracerebroventricular administration of streptozotocin.” Journal of neural transmission 105.8 (1998): 1045-1063.
  4. Rissanen, Anna, et al. “In mice tonic estrogen replacement therapy improves non‐spatial and spatial memory in a water maze task.” Neuroreport 10.6 (1999): 1369-1372.
  5. Kanoski, Scott E., and Terry L. Davidson. “Western diet consumption and cognitive impairment: links to hippocampal dysfunction and obesity.” Physiology & behavior 103.1 (2011): 59-68.
  6. Benito‐León, J., et al. “Obesity and impaired cognitive functioning in the elderly: a population‐based cross‐sectional study (NEDICES).” European Journal of Neurology 20.6 (2013): 899.
  7. Papanikolaou, Y., et al. “Better cognitive performance following a low-glycaemic-index compared with a high-glycaemic-index carbohydrate meal in adults with type 2 diabetes.” Diabetologia 49.5 (2006): 855-862.
  8. Smith, Michael A., and Jonathan K. Foster. “The impact of a high versus a low glycaemic index breakfast cereal meal on verbal episodic memory in healthy adolescents.” Nutritional neuroscience 11.5 (2008): 219-227.
  9. Kang, Young Sun. “Obesity associated hypertension: new insights into mechanism.” Electrolytes & Blood Pressure 11.2 (2013): 46-52.
  10. Friedel, S., et al. “Mutation screen of the brain derived neurotrophic factor gene (BDNF): identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention‐deficit/hyperactivity disorder.” American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 132.1 (2005): 96-99.
  11. Paglieri, Cristina, et al. “Hypertension and cognitive function.” Clinical and Experimental Hypertension 30.8 (2008): 701-710.
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